Transcript Slide 1

ADRENAL
Anwar Ali Jammah, MBBs, ABIM, FRCPC.
Objectives:
• Adrenal cortex and medulla Embryology.
• Gross structures.
• Blood supply, venous drainage, and nerves
supply .
• Adrenal hormones physiology.
Embryology of the Adrenal Gland
•
•
•
•
Cortexes develop from coelomic epithelium. They
appear in the 6th week.
Neural crest cells migrate into the centre of the
cortexes to develop the medulla. The cells differentiate
into sympathetic nerve cells.
Hormonal activity:
– Catecholamine production By the 10th week of fetal
life.
– Adrenal cortex by mid pregnancy.
The fetal adrenal is larger than the fetal kidney. At birth
it is about 20 times their relative size in the adult.
Neonatal adrenal gland
• Composed of 2 zones
– Fetal zone.
– Definitive zone: main site for cortisol synthesis.
• Fetal zone in this age is deficient in 3bhydroxysteroid dehydrogenase (3BHSD).
– The main product is DHEA and DHEAS the main
precursor of estrogen production from placenta
• (16-alfa hydroxylase (liver), 3BHSD and then Aromatase).
– Raising Estrogens (estrone, estradiol) level indicates
fetal and placenta wellbeing.
• Adrenal hypoplasia
– DAX1 gene mutation.
• Familial glucocorticoid deficiency
– ACTH receptor gene
– Melanocortin-2
Adrenal veins sampling
• Catheterizations and mixing samples
• Correct sampling and accurate recording
can be assured by the level of cortisol with
correlation to site of sampling.
– Rt. adrenal v. > Lt. adrenal v.
– Adrenal v : IVC ratio > 5:1
Sites of synthesis within adrenal gland
• Zona glomerulosa
– lacks 17α-hydroxylase activity
– Can not makes cortisol/androgens
• Zona fasiculata
• Zona reticularis
Lack P450aldo => can not make
aldosterone
P450aldo
Only in
zona
glomerulosa
Steroid synthesis
• Synthesized from cholesterol mainly from the circulating
LDL (80%).The rest from the free cholesterol within the
adrenal gland.
– LDL receptors present on cell surface
– ACTH, LH, FSH increase uptake and hydrolysis of cholesterol.
– Adrenal gland use other lipoprotiens (e.g. HDL) in this processed
• Pt. with abetalipoprotienemia (no LDL in serum) and Pt. with FHC
(defect in LDL receptors). They still have normal basal cortisol
synthesis.
Regulation
• ACTH controls the activity of the zona fasiculata, and zona reticularis
• Activates adenylate cyclase (AC), increase cAMP which increase PKA
result in:
–
–
–
–
Increase uptake lipoprotiens from plasma.
Increase hydrolysis of cholesteryl esters to free cholesterol.
Increase cholesterol synthesis within the gland.
Activate StAR which transfers cholesterol to mitochondria.
• This process activate:
– P450scc (rate-limiting step in cortisol synthesis) in the mitochondria. It
convert cholesterol to pregnenolone.
•
Pregnenolone is then transported to endoplasmic reticulum to complete the
steroid synthesis.
Hypothalmus-Pituitary-Adrenal Axis
Cortisol Circadian Rhythm
Feedback inhibition
• Glucocorticoid feedback occurs at:
– Pituitary.
– Hypothalamus.
• Two mechanisms:
– Fast (within minutes and last for <10 minutes)
• Depend on the rate of increase of GC.
• Mediated by non-cytosolic receptor mechanism.
– Delayed
• Depend on absolute GC level and the time of elevation.
• Mediated by nuclear receptor mechanism.
Cortisol Binding Systems
• Normally, <5% of circulating cortisol is free.
• Plasma has two cortisol-binding systems:
– High-affinity, low-capacity (80%)
Cortisol-binding globulin (CBG).
– Low-affinity, high-capacity (15%)
albumin.
• Cortisol binding to CBG is reduced in areas of inflammation, thus
increasing the local concentration of free cortisol.
• CBG is increased in:
–
–
–
–
Pregnancy.
Oral contraceptive
Hyperthyroidism
Diabetes
• Decreased in:
–
–
–
–
CLD
Nephritic syndrome
Hypothyroidism
Familial CBG deficiency
• Changes in CBG result in changes in total plasma cortisol
concentration but not the free level.
• With exception of prednisone, Synthetic glucocorticoid analogues
bind less efficiently to CBG, and bound mainly to Albumen( Dexa 75%
bound to Albumen).
Metabolism (Liver)
Less than 1% of unchanged cortisol secreted in urine
• Increase metabolism:
– Hyperthyroidism
– Hepatitis
– Drugs (rifampin, phenytoin, barbiturates)
• Decreased in:
– Hypothyroidism
– CLD
– Elderly
Metabolic effects
1.
2.
3.
4.
•
Promotes Gluconeogenesis.
Antagonizing the secretion and actions of insulin,
result in inhibiting peripheral glucose uptake.
increase hepatic glycogen synthesis and storage.
Increase lipolysis and protein catabolism to increase
FFA, AA.
Peripheral adipose tissue mass decreases, whereas
abdominal fat expand.
Calcium homeostasis
• Kidney:
– Decrease reabsorption of Ca. cause hypercalciuria
• Bone:
– Promotes osteoclastic bone resorption
– Inhibit osteoblast maturation and activity
• Inhibition of Bone formation is more at vertebral column
(trabecular bone), with less effect on long bones (compact
bone). (lumber>femur).
• Intestine:
– Inhibit Ca, Phosphate, Mg absorption by antagonizing
calcitriol.
Other endocrine effects
• Hypothalamus/pituitary
– Decrease response to GnRH
– Decrease GH secretion
– Decrease TSH secretion
• Adrenal Medulla
– Increase PNMT to increase epinephrine synthesis
– Increase response to catecholamines.
• Binding proteins
– Decrease CBG, SHBG, TBG
Anti-inflammatory properties
• Cortisol levels respond within minutes to stress
e.g. sepsis.
– Maintains vascular responsiveness to circulating
vasoconstrictors (catecholamines) and decrease
capillary permeability.
– Peripheral Leukocytosis by:
– release from the bone marrow.
– inhibition of their egress through the capillary wall.
– Decrease circulating Eosinophils and T cells
– { + Th2 (reset) and - Th1 (activate) } result in impairment of
cell-mediated immunity.
• Inhibit the production and action of the
inflammatory mediators e.g. lymphokines,
prostaglandins, interferon, IL-2, IL-1, IL-6
(antipyretic action), bradykinin, plateletactivating factor, and serotonin.
• Reduced adherence of macrophages to
vascular endothelium.
Aldosterone Regulation
• Stimulated by:
– (Main) Angiotensin II: via protein kinase C
– ACTH: via Cyclic AMP, protein kinase A
– K+: via Ca & voltage-gated Ca-channels
• Suppressed by:
– High Na intake
– hypokalemia K
• Binding system
– Aldosterone is bounded weekly to CBG.
– More to Albumin
– 30 to 50% of aldosterone is free.
• Metabolism
– Rapidly by liver and of free will appear in the urine in
small amount and it depende of the daily Na intake.
Aldosterone Action
•
•
Increase Na re absorption renal secretion of K+ and H+
Hyperaldosteronism Result in:
–
–
–
ECFV expansion
Hypokalemia
Alkalosis
• cortisol can bound to aldosterone receptors
• The presence of 11b-hydroxysteroid
dehydrogenase in the target tissue deactivate
cortisol.
– Licorice contain Glycyrrhetinic acid which
inhibits 11B-HSD2, and cause
minaralocorticoid excess.
– Mutation in 11B-HSD gene cause deficiency
in 11BHSD type2 (renal), cortisol can activate
the MC receptors.
– AD mutation in MC receptor result in partial
response to Aldosterone BUT full response to
other steroid (e.g. progesterone cause HTN in
pregnancy).
• Adrenal medulla anatomy and Embryology.
• Gross structures, histology, and innervations.
• Adrenal medulla hormones:
– Synthesis, release, and uptake.
– Regulation.
– Actions.
• Diagnosis of Pheochromocytoma.
Regulation of synthesis:
•First step: through tyrosine hydroxlase (rate-limiting ).
–Regulation is under negative feedback by NEpi and Epi.
•Last step: conversion from NorEpi to Epi through Phenylthanolamine
N-methyltransferase (PNMT)
–Requires high concentration of glucocorticoids in the central vein of the medulla.
•
Adrenal produces 80 % of Epinephrine and 20 % of Norepinephrine
– PNMT which is stimulated by high cortisol concentration in the adrenal
central vein.
•
Sympathetic nerve (nervous system) endings produce only Norepinephrine.
– No high cortisol concentration to activate (PNMT).
•
Pheochromocytoma secreting:
– Epinephrine (high metanephrine) likely to be found in the adrenal.
– Norepinephrine (high normetaniphrine) likely to be paraganglioma.
After adrenalectomy Adrenal medulla failure (Tb, hemorrhage):
– The plasma norepinephrine level is generally unchanged and
epinephrine level, falls to essentially zero.
– No need to replace epi.
In patients with adrenal insufficiency (low cortisol):
– They have epinephrine deficiency due to low cortisol in the central
adrenal vein.
•
•
• Each Chromaffine cell is
innervated by cholinergic
pre-sympathetic neurone,
which release
acetylcholine.
• Synapses are the
termination of fibers
whose cells bodies lie
mainly between T3 and
L3 in the spinal cord.
• Alpha 1 (eye, vessels of
skeletal muscles, heart )
– Epinephrine, Norepinephrine
– Increased free calcium
• Vasoconstriction, medriasis,
increase bladder sphincter
tone
• Alpha 2 (CNS, platelets,
pancreas and fat cell )
– Epinephrine, Norepinephrine
– Decreased cyclic AMP
• Inhabit NE. release, and insulin
release, increase lipolysis.
• Beta 2 (lung, vessels of skeletal
muscles, liver )
– Epinephrine
– Increase cyclic AMP
• Vasodilatation, bronchodilatation,
increase glycogenolysis and
increase glucagon release. uterine
relaxation.
• Beta 1 (heart)
– Epinephrine, Norepinephrine
– Increased cyclic AMP
• Tachycardia, and increase
myocardial contractility
•
About 70% of the norepinephrine and
epinephrine are conjugated to sulfate (inactive)
?? function.
•
Normal plasma level of free norepinephrine is
about 300 pg/mL (1.8 nmol/L) and free
epinephrine level, is normally about 30 pg/mL
(0.16 nmol/L).
•
The catecholamines half-life is about 2 minutes
in the circulation.
levels in human venous blood in various physiologic and pathologic states. In each case, the vertical
dashed line identifies the threshold plasma concentration at which detectable physiologic changes are
observed. (Modified and reproduced, with permission, from Cryer PE: Physiology and
pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303:436.)
Fate of Catecholamine
• Uptake-1 “mainly Norepinephrine”
– Post-ganglionic sympathetic nerve terminals.
– De-aminated by monoamine oxidase (MOA) in mitochondria.
– 85% reabsorped by nerve endings or target cells to become
available for re-use.
– Sites of drug action (e.g.. cocaine and antidepressants)
– Stimulated by progesterone
• Uptake-2 “Mainly Epinephrine”
– (blood cells, liver, kidney, and vascular smooth musle)
– Metabolized by O-methylation by catechol-O- methyl transferase
(COMT) to inactive end-products mainly metanephrine and
normetanephrine and VMA.
Secreted Catecholamines (urine)
• 50% metanephrines and normetanephrine.
• 35% VMA.
• 10% conjugated catecholamines.
• 5% free norepinephrine and epinephrine.